Mast cell–dependent CD8^þ T-cell recruitment mediates immune surveillance of intestinal tumors in Apc^Min/þ Mice

The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the adenomatous polyposis coli gene (Apc^Min/þ) displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2^–/^–Apc^Min/þ tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell–deficient ACKR2^–/^–SA^–/^–Apc^Min/þ mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth. Mast cells from ACKR2^–/^– mice showed elevated CCR2 and CCR5 expression and were also efficient in antigen presentation and activation of CD8^þ T cells. Mast cell–derived leukotriene B₄ (LTB₄) was found to be required for CD8^þ T lymphocyte recruitment, as mice lacking the LTB₄ receptor (ACKR2^–/^–BLT1^–/^–Apc^Min/þ) were highly susceptible to intestinal tumor-induced mortality. Taken together, these data demonstrate that chemokine-mediated recruitment of mast cells is essential for initiating LTB₄/BLT1-regulated CD8^þ T-cell homing and generation of effective antitumor immunity against intestinal tumors. We speculate that the pathway reported here underlies the positive prognostic significance of mast cells in selected human tumors.